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Histone demethylase

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https://www.readbyqxmd.com/read/28338398/dexamethasone-suppresses-jmjd3-gene-activation-via-a-putative-negative-glucocorticoid-response-element-and-maintains-integrity-of-tight-junctions-in-brain-microvascular-endothelial-cells
#1
Wonho Na, Jee Y Shin, Jee Y Lee, Sangyun Jeong, Won-Sun Kim, Tae Y Yune, Bong-Gun Ju
The blood-brain barrier (BBB) exhibits a highly selective permeability to support the homeostasis of the central nervous system (CNS). The tight junctions in the BBB microvascular endothelial cells seal the paracellular space to prevent diffusion. Thus, disruption of tight junctions results in harmful effects in CNS diseases and injuries. It has recently been demonstrated that glucocorticoids have beneficial effects on maintaining tight junctions in both in vitro cell and in vivo animal models. In the present study, we found that dexamethasone suppresses the expression of JMJD3, a histone H3K27 demethylase, via the recruitment of glucocorticoid receptor α (GRα) and nuclear receptor co-repressor (N-CoR) to the negative glucocorticoid response element (nGRE) in the upstream region of JMJD3 gene in brain microvascular endothelial cells subjected to TNFα treatment...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28338320/inhibitors-of-protein-methyltransferases-and-demethylases
#2
H Ümit Kaniskan, Michael L Martini, Jian Jin
Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets...
March 24, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28336409/development-and-crystallographic-evaluation-of-histone-h3-peptide-with-n-terminal-serine-substitution-as-a-potent-inhibitor-of-lysine-specific-demethylase-1
#3
Yuichi Amano, Masaki Kikuchi, Shin Sato, Shigeyuki Yokoyama, Takashi Umehara, Naoki Umezawa, Tsunehiko Higuchi
Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro...
March 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28327608/kdm4b-histone-demethylase-and-g9a-regulate-expression-of-vascular-adhesion-proteins-in-cerebral-microvessels
#4
Ji-Young Choi, Sang-Sun Yoon, Sang-Eun Kim, Sangmee Ahn Jo
Intercellular adhesion molecule 1 (ICAM1) mediates the adhesion and transmigration of leukocytes across the endothelium, promoting inflammation. We investigated the epigenetic mechanism regulating ICAM1 expression. The pro-inflammatory cytokine TNF-α dramatically increased ICAM1 mRNA and protein levels in human brain microvascular endothelial cells and mouse brain microvessels. Chromatin immunoprecipitation revealed that TNF-α reduced methylation of histone H3 at lysines 9 and 27 (H3K9 and H3K27), well-known residues involved in gene suppression...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28323958/jmjd3-is-crucial-for-female-avpv-rip-cre-neuron-controlled-kisspeptin-estrogen-feedback-loop-and-reproductive-function
#5
Anying Song, Shujun Jiang, Qinghua Wang, Jianghuan Zou, Zhaoyu Lin, Xiang Gao
The hypothalamic-pituitary-gonadal axis controls development, reproduction, and metabolism. While most studies were focusing on the hierarch from brain to gonad, many questions remain unresolved concerning the feedback from gonad to the central nervous system, especially on the potential epigenetic modification in hypothalamic neurons. In this report, we generated genetically modified mice lacking histone H3 lysine 27 demethylase JMJD3 in hypothalamic RIP-Cre neurons. The female mutant mice display late-onset obesity due to reduced locomotor activity and decreased energy expenditure...
March 9, 2017: Endocrinology
https://www.readbyqxmd.com/read/28319137/the-h3k27-demethylase-utx-regulates-adipogenesis-in-a-differentiation-stage-dependent-manner
#6
Kazushige Ota, Kit I Tong, Kouichiro Goto, Shuta Tomida, Akiyoshi Komuro, Zhong Wang, Kazuto Nishio, Hitoshi Okada
Understanding the molecular mechanisms that drive adipogenesis is important in developing new treatments for obesity and diabetes. Epigenetic regulations determine the capacity of adipogenesis. In this study, we examined the role of a histone H3 lysine 27 demethylase, the ubiquitously transcribed tetratricopeptide repeat protein on the X chromosome (Utx), in the differentiation of mouse embryonic stem cells (mESCs) to adipocytes. Using gene trapping, we examined Utx-deficient male mESCs to determine whether loss of Utx would enhance or inhibit the differentiation of mESCs to adipocytes...
2017: PloS One
https://www.readbyqxmd.com/read/28319067/the-histone-demethylase-kdm3a-and-its-downstream-target-mcam-promote-ewing-sarcoma-cell-migration-and-metastasis
#7
M Sechler, J K Parrish, D K Birks, P Jedlicka
Ewing Sarcoma is the second most common solid pediatric malignant neoplasm of bone and soft tissue. Driven by EWS/Ets, or rarely variant, oncogenic fusions, Ewing Sarcoma is a biologically and clinically aggressive disease with a high propensity for metastasis. However, the mechanisms underpinning Ewing Sarcoma metastasis are currently not well understood. In the present study, we identify and characterize a novel metastasis-promotional pathway in Ewing Sarcoma, involving the histone demethylase KDM3A, previously identified by our laboratory as a new cancer-promoting gene in this disease...
March 20, 2017: Oncogene
https://www.readbyqxmd.com/read/28314754/kdm6b-regulates-cartilage-development-and-homeostasis-through-anabolic-metabolism
#8
Jun Dai, Dongsheng Yu, Yafei Wang, Yishan Chen, Heng Sun, Xiaolei Zhang, Shouan Zhu, Zongyou Pan, Boon Chin Heng, Shufang Zhang, Hongwei Ouyang
OBJECTIVES: Epigenetic mechanisms have been reported to play key roles in chondrogenesis and osteoarthritis (OA) development. Here, we sought to identify specific histone demethylases that are involved and delineate the underlying mechanisms. METHODS: We screened the expression of 17 distinct histone demethylases by quantitative real time PCR (qRT-PCR) during chondrogenic differentiation of C3H10T1/2 cells. The role of Kdm6b in cartilage development was then analysed with transgenic Col2a1-CreER(T2);Kdm6b(f/f) ...
March 17, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28314201/inhibition-of-mirna-212-132-improves-the-reprogramming-of-fibroblasts-into-induced-pluripotent-stem-cells-by-de-repressing-important-epigenetic-remodelling-factors
#9
Nils Pfaff, Steffi Liebhaber, Selina Möbus, Abbas Beh-Pajooh, Jan Fiedler, Angelika Pfanne, Axel Schambach, Thomas Thum, Tobias Cantz, Thomas Moritz
MicroRNAs (miRNAs) repeatedly have been demonstrated to play important roles in the generation of induced pluripotent stem cells (iPSCs). To further elucidate the molecular mechanisms underlying transcription factor-mediated reprogramming we have established a model, which allows for the efficient screening of whole libraries of miRNAs modulating the generation of iPSCs from murine embryonic fibroblasts. Applying this model, we identified 14 miRNAs effectively inhibiting iPSC generation, including miR-132 and miR-212...
March 7, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28304334/kdm2-family-members-are-regulated-by-hif-1-in-hypoxia
#10
Michael Batie, Jimena Druker, Laura D'Ignazio, Sonia Rocha
Hypoxia is not only a developmental cue but also a stress and pathological stimulus in many human diseases. The response to hypoxia at the cellular level relies on the activity of the transcription factor family, hypoxia inducible factor (HIF). HIF-1 is responsible for the acute response and transactivates a variety of genes involved in cellular metabolism, cell death, and cell growth. Here, we show that hypoxia results in increased mRNA levels for human lysine (K)-specific demethylase 2 (KDM2) family members, KDM2A and KDM2B, and also for Drosophila melanogaster KDM2, a histone and protein demethylase...
March 17, 2017: Cells
https://www.readbyqxmd.com/read/28302961/getting-to-the-heart-of-the-matter-in-cancer-novel-approaches-to-targeting-cancer-stem-cells
#11
Hugh Colvin, Masaki Mori
Cancer is one of the leading causes of deaths worldwide. While cancers may initially show good response to chemotherapy or radiotherapy, it is not uncommon for them to recur at a later date. This phenomenon may be explained by the existence of a small population of cancer stem cells, which are inherently resistant to anti-cancer treatment as well as being capable of self-renewal. Therefore, while most of the tumour bulk consisting of cells that are not cancer stem cells respond to treatment, the cancer stem cells remain, leading to disease recurrence...
2017: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
https://www.readbyqxmd.com/read/28291760/gentle-fast-and-effective-crystal-soaking-by-acoustic-dispensing
#12
Patrick M Collins, Jia Tsing Ng, Romain Talon, Karolina Nekrosiute, Tobias Krojer, Alice Douangamath, Jose Brandao-Neto, Nathan Wright, Nicholas M Pearce, Frank von Delft
The steady expansion in the capacity of modern beamlines for high-throughput data collection, enabled by increasing X-ray brightness, capacity of robotics and detector speeds, has pushed the bottleneck upstream towards sample preparation. Even in ligand-binding studies using crystal soaking, the experiment best able to exploit beamline capacity, a primary limitation is the need for gentle and nontrivial soaking regimens such as stepwise concentration increases, even for robust and well characterized crystals...
March 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28290676/biochemical-characterization-of-ap-lyase-and-m-6-a-demethylase-activities-of-human-alkb-homolog-1-alkbh1
#13
Tina A Müller, Michael A Tobar, Madison N Perian, Robert P Hausinger
Alkbh1 is one of nine mammalian homologs of Escherichia coli AlkB, a 2-oxoglutarate-dependent dioxygenase that catalyzes direct DNA repair by removing alkyl lesions from DNA. Six distinct enzymatic activities have been reported for Alkbh1, including hydroxylation of variously methylated DNA, mRNA, tRNA, or histone substrates along with the cleavage of DNA at apurinic/apyrimidinic (AP) sites followed by covalent attachment to the 5'-product. The studies described here extend the biochemical characterization for two of these enzymatic activities using human ALKBH1: the AP lyase and 6-methyl adenine DNA demethylase activities...
March 14, 2017: Biochemistry
https://www.readbyqxmd.com/read/28286564/targeting-histone-methylation-for-colorectal-cancer
#14
REVIEW
Tao Huang, Chengyuan Lin, Linda L D Zhong, Ling Zhao, Ge Zhang, Aiping Lu, Jiang Wu, Zhaoxiang Bian
As a leading cause of cancer deaths worldwide, colorectal cancer (CRC) results from accumulation of both genetic and epigenetic alterations. Disruption of epigenetic regulation in CRC, particularly aberrant histone methylation mediated by histone methyltransferases (HMTs) and demethylases (HDMs), have drawn increasing interest in recent years. In this paper, we aim to review the roles of histone methylation and associated enzymes in the pathogenesis of CRC, and the development of small-molecule modulators to regulate histone methylation for treating CRC...
January 2017: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/28284523/demethylase-kdm6a-epigenetically-promotes-il-6-and-ifn-%C3%AE-production-in-macrophages
#15
Xia Li, Qian Zhang, Qingzhu Shi, Yin Liu, Kai Zhao, Qicong Shen, Yang Shi, Xingguang Liu, Chunmei Wang, Nan Li, Yuanfang Ma, Xuetao Cao
Molecular regulation of innate signal-initiated proinflammatory cytokine production has been extensively investigated. However, the roles of epigenetic modifiers and their underlying mechanisms in regulating innate inflammatory response and development of autoimmune diseases need to be further understood. Demethylase Kdm6a promotes gene transcription in cell-lineage specification through demethylating histone H3 lysine di/tri-methylation (H3K27me2/3), and loss of Kdm6a results in developmental defects. However, the function of Kdm6a in innate immunity and inflammation remains largely unknown...
March 8, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28278055/comparative-analyses-identify-molecular-signature-of-mri-classified-svz-associated-glioblastoma
#16
Chin-Hsing Annie Lin, Christopher T Rhodes, ChenWei Lin, Joanna J Phillips, Mitchel S Berger
Glioblastoma (GBM) is a highly aggressive brain cancer with limited therapeutic options. While efforts to identify genes responsible for GBM have revealed mutations and aberrant gene expression associated with distinct types of GBM, patients with GBM are often diagnosed and classified based on MRI features. Therefore, we seek to identify molecular representatives in parallel with MRI classification for group I and group II primary GBM associated with the subventricular zone (SVZ). As group I and II GBM contain stem-like signature, we compared gene expression profiles between these 2 groups of primary GBM and endogenous neural stem progenitor cells to reveal dysregulation of cell cycle, chromatin status, cellular morphogenesis, and signaling pathways in these 2 types of MRI-classified GBM...
February 22, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28276640/prospective-review-of-mesenchymal-stem-cells-differentiation-into-osteoblasts
#17
REVIEW
Priyanka Garg, Matthew M Mazur, Amy C Buck, Meghan E Wandtke, Jiayong Liu, Nabil A Ebraheim
Stem cell research has been a popular topic in the past few decades. This review aims to discuss factors that help regulate, induce, and enhance mesenchymal stem cell (MSC) differentiation into osteoblasts for bone regeneration. The factors analyzed include bone morphogenic protein (BMP), transforming growth factor β (TGF-β), stromal cell-derived factor 1 (SDF-1), insulin-like growth factor type 1 (IGF-1), histone demethylase JMJD3, cyclin dependent kinase 1 (CDK1), fucoidan, Runx2 transcription factor, and TAZ transcriptional coactivator...
March 9, 2017: Orthopaedic Surgery
https://www.readbyqxmd.com/read/28273462/negative-regulators-of-an-rnai-heterochromatin-positive-feedback-loop-safeguard-somatic-genome-integrity-in-tetrahymena
#18
Jan H Suhren, Tomoko Noto, Kensuke Kataoka, Shan Gao, Yifan Liu, Kazufumi Mochizuki
RNAi-mediated positive feedback loops are pivotal for the maintenance of heterochromatin, but how they are downregulated at heterochromatin-euchromatin borders is not well understood. In the ciliated protozoan Tetrahymena, heterochromatin is formed exclusively on the sequences that are removed from the somatic genome by programmed DNA elimination, and an RNAi-mediated feedback loop is important for assembling heterochromatin on the eliminated sequences. In this study, we show that the heterochromatin protein 1 (HP1)-like protein Coi6p, its interaction partners Coi7p and Lia5p, and the histone demethylase Jmj1p are crucial for confining the production of small RNAs and the formation of heterochromatin to the eliminated sequences...
March 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28265301/assessing-histone-demethylase-inhibitors-in-cells-lessons-learned
#19
Stephanie B Hatch, Clarence Yapp, Raquel C Montenegro, Pavel Savitsky, Vicki Gamble, Anthony Tumber, Gian Filippo Ruda, Vassilios Bavetsias, Oleg Fedorov, Butrus Atrash, Florence Raynaud, Rachel Lanigan, LeAnne Carmichael, Kathy Tomlin, Rosemary Burke, Susan M Westaway, Jack A Brown, Rab K Prinjha, Elisabeth D Martinez, Udo Oppermann, Christopher J Schofield, Chas Bountra, Akane Kawamura, Julian Blagg, Paul E Brennan, Olivia Rossanese, Susanne Müller
BACKGROUND: Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active 'probe' molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28263974/histone-demethylase-jmjd1a-promotes-urinary-bladder-cancer-progression-by-enhancing-glycolysis-through-coactivation-of-hypoxia-inducible-factor-1%C3%AE
#20
W Wan, K Peng, M Li, L Qin, Z Tong, J Yan, B Shen, C Yu
High aerobic glycolysis not only provides energy to cancer cells, but also supports their anabolic growth. JMJD1A, a histone demethylase that specifically demethylates H3K9me1/2, is overexpressed in multiple cancers, including urinary bladder cancer (UBC). It is unclear whether JMJD1A could promote cancer cell growth through enhancing glycolysis. In this study, we found that downregulation of JMJD1A decreased UBC cell proliferation, colony formation and xenograft tumor growth. Knockdown of JMJD1A inhibited glycolysis by decreasing the expression of genes participated in glucose metabolism, including GLUT1, HK2, PGK1, PGM, LDHA and MCT4...
March 6, 2017: Oncogene
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